Trifluoromethylation of Alkyl Radicals in Aqueous Solution

Article abstract of DOI:10.1021/jacs.7b06044

The copper-mediated trifluoromethylation of alkyl radicals is described. The combination of Et₃SiH and K₂S₂O₈ initiates the radical reactions of alkyl bromides or iodides with BPyCu(CF₃)₃ (BPy = 2,2′-bipyridine) in aqueous acetone at room temperature to afford the corresponding trifluoromethylation products in good yield. The protocol is applicable to various primary and secondary alkyl halides and exhibits wide functional group compatibility. A mechanism involving trifluoromethyl group transfer from Cu(II)-CF₃ intermediates to alkyl radicals is proposed.

Full text of DOI:10.1021/jacs.7b06044

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Communication
Trifluoromethylation of Alkyl Radicals in Aqueous Solution
Haigen Shen, Zhonglin Liu, Pei Zhang, Xinqiang Tan, Zhenzhen Zhang, and Chaozhong Li
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Haigen Shen,a Zhonglin Liu,a Pei Zhang,a Xinqiang Tan,a Zhenzhen Zhang,a and Chaozhong Li*, a, b
a Key Laboratory of Organofluorine Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences, Shang-
hai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, and b
School of Materials and Chemical Engineering, Ningbo University of Technology, No. 201 Fenghua Road, Ningbo 315211,
P. R. China.
Supporting Information Placeholder
protocol for the trifluoromethylation of alkyl radicals that in-
volves CF3 group transfer.
ABSTRACT: The copper-mediated trifluoromethylation of alkyl
radicals is described. The combination of Et3SiH and K2S2O8
initiates the radical reactions of alkyl bromides or iodides with
BPyCu(CF3)3 (BPy = 2,2’-bipyridine) in aqueous acetone at room
temperature to afford the corresponding trifluoromethylation
products in good yield. The protocol is applicable to various pri-
mary and secondary alkyl halides and exhibits wide functional
group compatibility. A mechanism involving trifluoromethyl
group transfer from Cu(II)–CF3 intermediates to alkyl radicals is
proposed.
Scheme 1. Trifluoromethylation for C(sp3)–CF3 Fromation
Fluorine is recognized as a key element in pharmaceuticals, ag-
rochemicals and materials. The incorporation of trifluoromethyl
groups into organic molecules has a profound effect on their
lipophilicity, permeability and metabolic stability. As a conse-
quence, the development of new trifluoromethylation methods
that involve mild conditions has received considerable attention
and significant progress has been achieved in this area in the past
decade.1–3 In particular, a number of methods have been devel-
oped for C(sp3)–CF3 bond formation. These methods generally
fall into the following three categories based on the type of CF3
intermediates involved: (a) nucleophilic trifluoromethylation with
trifluoromethyl anions derived from reagents such as Me3SiCF3
(Ruppert–Prakash reagent),4 FSO2CF2CO2Me (Chen reagent)5 or
A common approach for the generation of alkyl radicals is the
treatment of alkyl halides with reducing agents such as tin or sili-
con hydrides. Thus, we selected 6-bromohexyl tosylate (Br-1a)
and triethylsilane as
a model system to explore radical
trifluoromethylation (Table 1). The use of Br-1a was also de-
signed to help clarify the mechanism of substitution as the
tosylate moiety should remain inert under radical
trifluoromethylation but should be as reactive as the bromide un-
der nucleophilic trifluoromethylation conditions.12, 13 With regard
to the CF3 source, we chose to investigate the use of the complex
BPyCu(CF3)3 (BPy = 2,2’-bipyridine), recently developed by
Grushin et al.14 Bromide Br-1a was treated with excess Et3SiH
and BPyCu(CF3)3 in acetonitrile at room temperature in the pres-
ence of a peroxide initiator such as di-tert-butyl peroxyoxalate
(DBPO), di-tert-butyl peroxide (DTBP), benzoyl peroxide (BPO)
or K2S2O8 (entries 1–6, Table 1). Pleasingly, the expected
trifluoromethylation product 1a was obtained in 11% yield when
K2S2O8 was used as the initiator. Switching the solvent to aqueous
acetonitrile or acetone significantly increased the yield of the
process (entries 7–10, Table 1) and an 80% yield of 1a was ob-
tained when acetone–water (2:1) was employed as solvent. The
dramatic, beneficial effect of water may be attributed to the im-
proved solubility of K2S2O8 in aqueous solution. In contrast, no
1a was detected when biphasic CH2Cl2/H2O was used as solvent
(entry 11, Table 1). After further adjustment of the reagent ratios
(entries 12–16, Table 1), the use of a stoichiometric amount of
BpyCu(CF3)3 as the CF3 source and Et3SiH (6 equiv)/K2S2O8 (4
equiv) as the initiation system, gave 1a in almost quantitative
yield (entry 14, Table 1). Use of other silanes in place of Et3SiH
led to lower yields of the product (entries 17–20, Table 1) and the
product of direct reduction, n-hexyl tosylate, was obtained in 47%
(Ph3P)3CuCF3
(Grushin
reagent);6
(b)
electrophilic
trifluoromethylation2 of carbon-centered nucleophiles with elec-
trophilic CF3 reagents such as the Umemoto reagent,7 Togni’s
reagent8 or Shibata reagent;9 (c) addition of trifluoromethyl radi-
cals3 to unsaturated moieties such as alkenes, alkynes or
isonitriles (Scheme 1, a–c). Although the trifluoromethylation of
carbon-centered nucleophiles and electrophiles is well document-
ed, the trifluoromethylation of carbon-centered radicals remains
largely unexplored (Scheme 1d). Of the few relevant reports,
Gölitz and de Meijere reported that the decomposition of 1-alkyl-
2-trifluoromethyldiazenes (R-N=N-CF3) under UV irradiation in
highly viscous solvents, such as t-butanol or hexadecane, led to
products of radical coupling (R–CF3) in low to moderate yield.10
Furthermore, Qing and coworkers described the copper-mediated
1,2-bis(trifluoromethylation) of alkenes using CF3SO2Na and t-
BuOOH and involving the addition of CF3 radical to alkenes fol-
lowed by coupling of the resultant radical with another CF3 radi-
cal.11 Despite these reports, it is important to note that the cross
coupling of two transient radicals is unlikely to be general and
thus is of limited value in synthesis. Herein we describe a new
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when (TMS)3SiH was used. Finally, control experiments indicated
that both Et3SiH and K2S2O8 were required for the
We next extended the method to the trifluoromethylation of
secondary alkyl bromides (Scheme 3). As for the reaction of pri-
mary alkyl bromides, secondary alkyl bromides Br-2 underwent
smooth trifluoromethylation under the optimized conditions and
gave the expected products of trifluoromethylation 2a–2o in satis-
factory yield. Again, broad substrate scope and wide functional
group compatibility was observed. Of particular note,
trifluoromethylated alkyl azide (2f), amino acid derivative (2j),
and steroid (2n) were obtained from the corresponding bromides,
thus illustrating the suitability of this method for the late-stage
modification of complex molecules. Moderate diastereocontrol
was observed in the preparation of the trifluoromethylated prod-
ucts 2j, 2l and 2n. Tertiary (e.g. 2m) and primary alkyl chlorides
(e.g. 2k) were unreactive towards trifluoromethylation. Interest-
ingly, when the gem-dibromide substrate (Br-2o) was employed,
the corresponding mono-trifluoromethylation product 2o was
trifluoromethylation (entries 21 and 22, Table 1). Notably, 1a was
14
not formed when Bu4NCu(CF3)4 or an electrophilic CF3 reagent
(e.g. Tongi’s reagent, Umemoto reagent or Shibata reagent) was
used in place of BPyCu(CF3)3.
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Table 1. Optimization of Reaction Conditions
BPyCu(CF3)3
(x equiv)
CF3
Br
TsO
TsO
silane, peroxide
solvent, rt, 12 h
Br-1a
1a
ent
rya
1
silane
(equiv)
peroxide
(equiv)
DBPO (3)
DTBP (3)
DTBP (3)
BPO (3)
yield
(%)b
1
4
9
x
solvent
obtained in 83% yield with only
trifluoromethylation observed.
a
trace of bis-
2
2
2
2
2
2
2
2
2
2
2
2
2
1
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (5)
Et3SiH (6)
Et3SiH (6)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2
3c
4
Scheme 2. Trifluoromethylation of Primary Alkyl Bro-
mides
0
5c
6
BPO (3)
K2S2O8 (3)
49
11
65
80
75
30
0
BPyCu(CF3)3
Et3SiH, K2S2O8
7
8
9
10
11
12
13
14
K2S2O8 (3) MeCN/H2O (2:1)
K2S2O8 (3) Me2CO/H2O (2:1)
K2S2O8 (3) Me2CO/H2O (4:1)
K2S2O8 (3) Me2CO/H2O (1:1)
K2S2O8 (3) CH2Cl2/H2O (2:1)
K2S2O8 (3) Me2CO/H2O (2:1)
K2S2O8 (4) Me2CO/H2O (2:1)
RCH2 Br
RCH2 CF3
1, yielda, b
Me2CO/H2O (2:1)
rt, 12 h
Br-1
CF3
PhthN
CF3
RO
n
1a (R = Ts), 95%; 1b (R = Bs), 88%
1d (n = 3), 90%; 1e (n = 2), 87%
91
94
1c
(R = p-Cl-C6H4SO2), 90%
1f
1g
(n = 1), 83%;
(n = 0), 56%
CF3
Et3SiH (6) K2S2O8 (4) Me2CO/H2O (2:1) 98d
CF3
RHN
n
HO2C
15 0.8
16 0.6
Et3SiH (6)
Et3SiH (6)
K2S2O8 (4) Me2CO/H2O (2:1)
K2S2O8 (4) Me2CO/H2O (2:1)
90
80
76
9e
0
0
0
0
1h
(R = p-Cl-C6H4SO2), 87%
1i (n = 5), 89%
17
18
19
20
21
22
1
1
1
1
1
1
Et2SiH2 (6) K2S2O8 (4) Me2CO/H2O (2:1)
(TMS)3SiH (6) K2S2O8 (4) Me2CO/H2O (2:1)
Ph3SiH (6)
(MeO)3SiH (6) K2S2O8 (4) Me2CO/H2O (2:1)
none
Et3SiH (6)
Ar
O
CF3
DPTBSO
CF3
1j
(Ar = p-Cl-C6H4), 55%
1k, 68%
K2S2O8 (4) Me2CO/H2O (2:1)
O
O
K2S2O8 (4) Me2CO/H2O (2:1)
none Me2CO/H2O (2:1)
CF3
CF3
n
Cl
O
4
a
1m, 84%
1l (n = 7), 83%
Reaction conditions: Br-1a (0.1 mmol), BPyCu(CF3)3, silane,
peroxide, solvent (3 mL), rt, 12 h. b 19F NMR yield (with PhCF3
O
c
Ph
O
CF3
as the internal standard) based on Br-1a. The reaction was car-
CO2Me
ried out under UV (365 nm) photolysis. d Isolated yield: 95%. e n-
CF3
O
1o, 84%
Hexyl tosylate was isolated in 47% yield.
1n, 89%
O
O
O
O
With the optimized conditions in hand (entry 14, Table 1), we
set out to explore the scope of the method. As shown in Scheme 2,
the radical trifluoromethylation of various primary alkyl bromides
Br-1 proceeded smoothly in aqueous solution at room tempera-
ture and furnished products 1a–1t in good to excellent yield. The
presence of a wide range of functional groups was tolerated by the
process. For example, ethers, silyl ethers, ketones, esters, nitriles,
amides, imides, sulfonates, sulfonamides, free carboxylic acids,
aryl and alkyl chlorides all proved to be compatible with the reac-
tion. This excellent functional group compatibility allows the
direct modification of complex molecules such as carbohydrates,
as exemplified by the efficient preparation of 1q. In contrast, pri-
mary alkyl chlorides were inert under the reaction conditions. For
example, trifluoromethylated alkyl chloride 1m was obtained in
high yield.
CF3
NC
Ph Ph
CF3
O
O
1p, 73%
1q, 86%
O
tBu
Boc
O
N
CF3
CF3
CF3
Ph
O
c
1t, 76%
1r, 61%
1s
, 55%
a Reaction conditions: Br-1 (0.2 mmol), BPyCu(CF3)3 (0.2 mmol),
Et3SiH (1.2 mmol), K2S2O8 (0.8 mmol), acetone (4 mL), H2O (2
mL), rt, 12 h. b Isolated yield based on Br-1. c Solvent: acetone (4
mL), H2O (1 mL).
In addition to being general, the radical trifluoromethylation is
operationally simple and the conditions used are extremely mild.
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b
c
It is also important to note that the few reports of nucleophilic
mL), UV (365 nm), rt, 12 h. Isolated yield based on I-1. Ar =
p-Cl-C6H4.
trifluoromethylation of simple alkyl halides either require harsh
reaction conditions or suffer from limited substrate scope.12 Thus,
this radical trifluoromethylation approach complements known
routes to related targets.
In contrast to primary and secondary alkyl bromides, tertiary
alkyl bromides did not give the products of trifluoromethylation.
Instead, byproducts presumably derived from the corresponding
tertiary alkyl radicals were obtained (see the Supporting Infor-
mation for details). It is likely that the trifluoromethylation of
tertiary alkyl radicals is retarded by steric effects.
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Scheme 3. Trifluoromethylation of Secondary Alkyl Bro-
mides
We then extended the method to alkyl iodides. Given that alkyl
iodides are even more reactive than alkyl bromides towards
triethylsilyl radicals,15 it was surprising to find that the reaction of
alkyl iodides under the above optimized conditions produced low
yields of the expected trifluoromethylation products (20 ~ 30%)
and the alkyl iodides (60 ~ 70%) were recovered. However, re-
optimized reaction conditions, involving UV irradiation (365 nm),
delivered the expected trifluoromethylation products 1 and 2 in
satisfactory yields from the corresponding alkyl iodides I-1. This
protocol is applicable to both primary and secondary alkyl iodides
(Scheme 4).
Scheme 5. Mechanistic Experiments
a Reaction conditions: Br-2 (0.2 mmol), BPyCu(CF3)3 (0.2 mmol),
Et3SiH (1.2 mmol), K2S2O8 (0.8 mmol), acetone (4 mL), H2O (2
mL), rt, 12 h. b Isolated yield based on Br-2. c Solvent: acetone (4
d
e
f
mL), H2O (1 mL). trans/cis = 70:30. trans/cis = 68:32. dr =
80:20.
Scheme 4. Trifluoromethylation of Alkyl Iodides
To gain further insight into the trifluoromethylation, mecha-
nistic studies were carried out (Scheme 5). The reaction of 2-(N-
allyl-N-tosylamino)ethyl bromide (3) under the optimized condi-
tions afforded the cyclized product 4 in 55% yield (Eq. 1). When
cyclopropylmethyl bromide 5 was subjected to the optimized
conditions for the trifluoromethylation of alkyl bromides, the ring-
opening product 6 was isolated in 25% yield (5 was recovered in
25% yield) (Eq. 2). These radical clock experiments16 unambigu-
ously demonstrated the intermediacy of alkyl radicals. To probe
the identity of the species responsible for the trifluoromethylation
of alkyl radicals, BPyCu(CF3)3 was directly treated with ethyl
radicals formed from Et3B under an O2 atmosphere. The for-
mation of 1,1,1-trifluoropropane (7) was not detected (Eq. 3). In
contrast, when a mixture of Cu(OTf)2, BPy, TMSCF3 and CsF in
1:1:2.5:2.5 ratio was treated with Et3B/O2 in acetonitrile at room
temperature, the product 7 was formed (35% yield by 19F NMR)
(Eq. 4). These two experiments suggest that the active
a
Reaction conditions: I-1 (0.2 mmol), BPyCu(CF3)3 (0.4 mmol),
Et3SiH (1.2 mmol), K2S2O8 (0.8 mmol), acetone (4 mL), H2O (1
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trifluoromethylation agent is likely to be a Cu(II)–CF3 complex
rather than a Cu(III)–CF3 complex. Finally, the role of UV irra-
diation in the reactions of alkyl iodides was also probed. As
shown in Eq. 5, the photolysis of BPyCu(CF3)3 in the presence of
an equimolar amount of TEMPO (2,2,6,6-tetramethylpiperidine-
Notes
6
7
8
9
The authors declare no competing financial interests.
ACKNOWLEDGMENT
N-oxyl radical) afforded
8 in 68% yield, indicating that
This project was supported by the National Basic Research Pro-
gram of China (973 Program) (Grant 2015CB931900), by the
National Natural Science Foundation of China (Grants 21421002,
21472220, 21532008, and 21602239), and by the Strategic Priori-
ty Research Program of the Chinese Academy of Sciences (Grant
XDB20020000). We thank Prof. David J. Procter of University of
Manchester for his generous help in revising the manuscript.
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trifluoromethyl radicals are produced from BPyCu(CF3)3 upon
photostimulation.17
A plausible mechanism for the trifluoromethylation is shown
in Figure 1. Interaction of Et3SiH with persulfate generates the
triethylsilyl radical that abstracts a bromine atom from alkyl bro-
mide to produce the corresponding alkyl radical. Subsequent
trifluoromethyl group transfer from a Cu(II)–CF3 complex (such
as A)18 to the alkyl radical affords the trifluoromethylation prod-
uct and a Cu(I) complex (such as B). Furthermore, complex A
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may be regenerated by comproportionation of
B
with
BPyCu(CF3)3. In the reaction of alkyl iodides, Et3SiI generated by
iodine atom abstraction by the triethylsilyl radical may undergo
hydrolysis in aqueous solution to give HI. I2 may then be pro-
duced by K2S2O8 oxidation of HI, and I2 may act as the radical
chain suppressant.19 Such a phenomenon is well documented in
iodine atom transfer radical addition reactions.19 Upon UV irra-
diation, the trifluoromethyl radical is generated and this may serve
as a scavenger for I2, forming CF3I, thus allowing the radical
trifluoromethylation to proceed smoothly. Further investigations
on the mechanism of radical trifluoromethylation are certainly
underway.
Figure 1. Proposed mechanism for the trifluoromethylation of
alkyl radicals.
In conclusion, we have developed a practical protocol for the
trifluoromethylation of alkyl halides formed in situ from alkyl
halides. As the procedure is operationally simple, broad in scope,
tolerant of sensitive functional groups, and utilizes the readily
available Grushin reagent BPyCu(CF3)3, the method should find
application in the synthesis of important trifluoromethylated mol-
ecules. A catalytic variant of the radical trifluoromethylation is
currently under development in our laboratory.
ASSOCIATED CONTENT
Supporting Information
Full experimental details, characterizations of new compounds,
and copies of 1H, 13C and 19F NMR spectra (PDF). The material is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* E-mail: clig@mail.sioc.ac.cn
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